PI 3-kinases (PI3Ks) generate lipids in cell membranes which bind a variety of intracellular protein effectors, affecting their localization and/or activity. The PI3K signalling axis is one of the most frequently deregulated pathways in cancer. Mammals have 8 isoforms of PI3K, divided into three classes. The class I PI3Ks consist of a p110 catalytic subunit (p110alpha, p110beta, p110delta and p110gamma) bound to a regulatory subunit. Recent work has revealed that PI3K isoforms have surprisingly distinct roles in biology. Compared to the other class I PI3Ks, the organismal role and signalling of p110beta is poorly understood. My preliminary data point to a new and unexpected role of p110beta isoform in the control of breast cancer invasion and endosomal functions. My hypothesis is that these two phenomena are interconnected. In this proposal, I seek to investigate the role and mechanism of action of p110beta in breast cancer cell invasion. I will determine effectors downstream of p110beta involved in the control of cancer cell shape, motility and invasion and unravel molecular details of how p110beta transmits signals in the cell, with a focus on endosomal biology in the context on cell invasion. This will be achieved combining both cell-based in vitro 3D-invasion techniques using p110beta-selective pharmacological inhibitors and in vivo models of cancer invasion using mice expressing an inactive p110beta. An siRNA screen as well and advanced techniques of microscopy, biochemistry and cell biology will be performed. The results of these studies have implications for the fundamental understanding of PI3K function and the use of PI3K isoform-selective inhibitors in cancer.
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